High-dose Continuous Infusion Research Articles

High-Dose Continuous Infusion Plus Pulse Interleukin-2 and Famotidine in Metastatic Kidney Cancer

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.

High-Dose Continuous Infusion Plus Pulse Interleukin-2 and Famotidine in Melanoma

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.

High-Dose Continuous Infusion Plus Pulse Interleukin-2 and Famotidine in Melanoma

s for the 19th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer, San Francisco, California, November 4-7, 2004: Adoptive Immunotherapy

Correlation between Pulmonary Edema and Response of Pulmonary Metastases to High Dose Continuous Infusion Interleukin-2 in Metastatic Melanoma and Kidney Cancer

Correlation between Pulmonary Edema and Response of Pulmonary Metastases to High Dose Continuous Infusion Interleukin-2 in Metastatic Melanoma and Kidney Cancer

Treatment of Patients Age 70 and over with Inpatient High-Dose Continuous Infusion Interleukin-2 for Metastatic Melanoma and Kidney Cancer

Treatment of Patients Age 70 and over with Inpatient High-Dose Continuous Infusion Interleukin-2 for Metastatic Melanoma and Kidney Cancer

Phase II study of liposomal daunorubicin and ifosfamide (IDx) as first line chemotherapy in soft tissue sarcoma

9011 Background: Anthracycline/ifosfamide combination is the most effective chemotherapy in soft tissue sarcoma. To improve tolerability and potentially efficacy of this combination we combined liposomal daunorubicin (L-Dauno) with high dose continuous infusion ifosfamide. Methods: In a single-arm phase II study 40 patients were enrolled with a median age of 57 years (19 to 78 years). Treatment regimen was L-Dauno 100 mg/m2 and ifosfamide 5 g/m2 over 24 h every 4 weeks with G-CSF support. Initially, 5 patients were included after failure of a doxorubicin/ifosfamide regimen, but none of these responded. Subsequently, 35 patients were treated first line. Results: A total of 115 cycles (range 1 to 7) were given. Toxicity was tolerable with 5 episodes (4,8 % of cycles) of ifosfamide related CNS toxicity grade II and 9 episodes (8,6 % of cycles) of neutropenic fever. Treatment had to be terminated due to a pseudo-allergic reaction to L-Dauno in one patient. One patient had ifosfamide related acute renal failure and was further treated with L-Dauno alone. No other non-hematological toxicity exceeding grade II was observed. Eleven (31,4 %) out of 35 patients without pretreatment achieved a PR, all after 2 treatment cycles, 6 patients (17,1 %) had stable disease and 12 patients (34,3 %) progressed; 6 patient were not evaluable (2 treatment unrelated early deaths, 2 lost to follow up, 1 adjuvant treatment, 1 to early to evaluate). Median time to progression was 10 months, median overall survival 16 months. PR with respect to histology was: 4/7 PNET, 1/6 leiomyosarcoma, 2/4 liposarcoma, 1/2 synovial sarcoma, 1/3 pleomorphic sarcoma, 1/1 malignant histiocytoma and 1/2 carcinosarcoma. Four of the responding patients received a consolidating high-dose-chemotherapy with subsequent stem cell support. Conclusions: IDx is a well tolerated and highly active chemotherapy regimen for first line treatment of soft tissue sarcoma, even in elderly patients. Randomized studies with this regimen are warranted. No significant financial relationships to disclose.

P1111 The assessment of cardiac toxicity of high-dose continuous infusion 5-fluorouracil with ultrasonic myocardial tissue characterization

P1111 The assessment of cardiac toxicity of high-dose continuous infusion 5-fluorouracil with ultrasonic myocardial tissue characterization

CPU 86017 suppresses tachyarrhythmias induced by ouabain and myocardial infarction: Concentrations in plasma and different areas of the heart in dogs

AbstractCPU 86017 (p‐chlorobenzyl‐tetrahydroberberine) a derivative of berberine, possesses an antiarrhythmic effect against arrhythmias in animal models. Two canine arrhythmia models were established by i.v. infusion of ouabain and two‐stage ligation of coronary artery to generate sustained ventricular tachyarrhythmias in dogs. In the ouabain model CPU 86017 was infused at 0.96mg/kg divided into two doses of 0.36 and 0.6mg/kg; tachycardia was completely suppressed and reversed to control sinus rhythm. The canine heart was infarcted by two‐stage ligation of the anterior coronary artery and cardiac tachycardia occurred 20h after coronary ligation. A total dose of 0.5, 0.7, and 1.0mg/kg i.v. infusion of CPU 86017 was effective to suppress arrhythmic scores (0–7 score system) from the untreated 5.2±0.7 to 3.8±0.5, (P<0.05), 3.9±1.9 (P<0.05) and 2.6±2.0(P<0.01), respectively, and i.v. amiodarone 5mg/kg reduced arrhythmic scores to 2.3±1.3 (P<0.01). There was a counterclockwise hysteresis loop of the pharmacokinetic/pharmacodynamic relationship in both models attributed to a small Keo value. Concentrations were not different in the outer, middle, and inner layers of the left ventricle, but higher in the working myocardium against the SA node and AV node. They were also different in the myocardial levels in the infarcted, risk, and noninfarcted regions where concentrations were 0.267±0.09μg/ml, 0.948±0.399μg/ml, and 1.371±0.433μg/ml, respectively. By continuous infusion of high doses in ouabain‐receiving dogs the PR interval and QTc (QTc = QT/(R‐R)) were prolonged by 27.5% and 24.5%, respectively (P<0.001). The accumulation in the myocardium of CPU 86017 was evident against the rapid decrease in plasma levels. The toxicity to the heart by high doses of CPU 86017 is principally due to cardiac block and cardiac arrest rather than torsade de pointes. Drug Dev. Res. 58:131–137, 2003. © 2003 Wiley‐Liss, Inc.

Safety and efficacy of an accelerated dobutamine stress echocardiography protocol in the evaluation of coronary artery disease

Although dobutamine requires up to 10 minutes to achieve steady state, dobutamine stress echocardiography is routinely performed using stepwise increments at 3-minute intervals. Consequently, the full effect of any infusion rate is not attained before the dobutamine dose is advanced to the next level. This study sought to test the safety and efficiency of high-dose continuous dobutamine infusion. One hundred consecutive patients underwent an accelerated protocol using a constant infusion of 50 μg/kg/min. In the absence of a stress echocardiographic end point (≥85% of maximal predicted heart rate, new wall motion abnormalities, hypotension, arrhythmia, or intolerable symptoms), dobutamine infusion was discontinued at 10 minutes. Hemodynamic responses and adverse effect profile were compared with 100 patients who underwent a standard stepwise dobutamine stress protocol. Peak heart rate (140 ± 16 vs 140 ± 19 beats/min, p = 0.95) and systolic blood pressure (169 ± 32 vs 162 ± 31 mm Hg, p = 0.08) were similar in both protocols. Accelerated dobutamine administration produced a rapid increase in heart rate (12.5 ± 6.2 vs 5.7 ± 2.6 beats/min, p <0.001), and a substantial reduction in test duration (6.4 ± 2.4 vs 12.9 ± 3.0 minutes, p <0.001). The mean weight-adjusted cumulative dobutamine dose was lower in the accelerated protocol group (320 ± 111 vs 353 ± 133 μg/kg, p = 0.016). No significant differences were noted between the 2 groups with respect to various side effects. These data demonstrate that a high-dose, single-stage dobutamine echocardiographic stress protocol is a feasible, well-tolerated alternative to standard dobutamine stress echocardiography, and results in a substantial reduction in test time while maintaining a low complication rate.

Direct Graft Puncture with Use of a Crossed Catheter Technique for Thrombolysis of Peripheral Bypass Grafts

To determine the efficacy and safety of direct graft puncture of peripheral arterial bypass grafts with placement of retrograde and antegrade catheters within the graft for thrombolytic therapy. This study also evaluated potential clinical benefit to patients. A retrospective study was performed on 19 patients with 24 peripheral bypass grafts and lower extremity ischemia of less than 1 month duration. Thrombolysis was performed with a continuous high-dose infusion of urokinase. Successful lysis was defined as greater than 95% clot dissolution with antegrade flow within the graft. Technical success was achieved in 17 of 19 patients (89%). The complexity of operative intervention was diminished in 12 of 19 patients (63%). The major complication rate (16%) was significantly higher and, therefore, this technique has a role for patients in whom traditional access is not optimal, such as in those in whom access cannot be achieved or in those with long bypass grafts. Direct graft puncture with placement of catheters across the proximal and distal anastomoses of bypass grafts is a safe method of access, with a major complication rate similar to conventional access techniques. This mode of graft access demonstrates efficacious thrombolysis and acts as a conduit for ancillary procedures.

Role of Iphosphamide in the treatment of breast cancer

Breast cancer is the most frequent solid tumor in women. Predictive and prognostic factors play an important role in the treatment of this cancer. We focused on high risk and heavily pre-treated metastatic breast cancer patients, trying to find the best combination of cytotoxic drugs with high efficacy and low toxicity. Ifosfamide is chemically related to nitrogen mustard and is a synthetic analogue of cyclophosphamide. Ifosfamide has a wide range of antitumor activity. Since ifosfamide as monotherapy has introduced significant tumor reduction in 1(st) line chemotherapy for advanced breast cancer, some studies started with high-dose continuous infusion of ifosfamide,or combined with paclitaxel or vinorelbine. Patients with poor prognosis primary breast cancer treated with high-dose chemotherapy supported by peripheral blood progenitor cell (PBSC) transplantation have lower risk for local relapse and longer disease-free-survival. Ifosfamide working in the mobilization regimen has effective anti-tumor activity while mobilizing sufficient PBPCs in the majority of patients. In combination with other cytotoxics showed to be effective in high-dose protocols.

High Dose Ifosfamide in Combination with Etoposide and Epirubicin Followed by Autologous Stem Cell Transplantation in the Treatment of Relapsecd/Refractory Hodgkin's Disease: a Report on Toxicity and Efficacy On behalf of the Scotland and Newcastle Lymphoma Group

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of 'ifosfamide at a dose of 9g/m2 over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M18F) with a median age of 28 years (range 13–45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Hae-matological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with diffcult Hodgkin's disease and warrants further study.

Treatment of vancomycin-resistant Enterococcus faecium with RP 59500 (quinupristin-dalfopristin) administered by intermittent or continuous infusion, alone or in combination with doxycycline, in an in vitro pharmacodynamic infection model with simulated endocardial vegetations.

Quinupristin-dalfopristin is a streptogramin antibiotic combination with activity against vancomycin-resistant Enterococcus faecium (VREF), but emergence of resistance has been recently reported. We studied the activity of quinupristin-dalfopristin against two clinical strains of VREF (12311 and 12366) in an in vitro pharmacodynamic model with simulated endocardial vegetations (SEVs) to determine the potential for resistance selection and possible strategies for prevention. Baseline MICs/minimal bactericidal concentrations (microg/ml) for quinupristin-dalfopristin, quinupristin, dalfopristin, and doxycycline were 0.25/2, 64/>512, 4/512, and 0.125/8 for VREF 12311 and 0.25/32, 128/>512, 2/128, and 0.25/16 for VREF 12366, respectively. Quinupristin-dalfopristin regimens had significantly less activity against VREF 12366 than VREF 12311. An 8-microg/ml simulated continuous infusion was the only bactericidal regimen with time to 99.9% killing = 90 hours. The combination of quinupristin-dalfopristin every 8 h with doxycycline resulted in more killing compared to either drug alone. Quinupristin-dalfopristin-resistant mutants (MICs, 4 microg/ml; resistance proportion, approximately 4 x 10(-4)) emerged during the quinupristin-dalfopristin monotherapies for both VREF strains. Resistance was unstable in VREF 12311 and stable in VREF 12366. The 8-microg/ml continuous infusion or addition of doxycycline to quinupristin-dalfopristin prevented the emergence of resistance for both strains over the 96-h test period. These findings replicated the development of resistance reported in humans and emphasized bacterial factors (drug susceptibility, high inoculum, organism growth phase) and infectious conditions (penetration barriers) which could increase chances for clinical resistance. The combination of quinupristin-dalfopristin with doxycycline and the administration of quinupristin-dalfopristin as a high-dose continuous infusion warrant further study to determine their potential clinical utility.

Clinical and immunomodulatory effects of repetitive 2-day cycles of high-dose continuous infusion IL-2.

High-dose interleukin-2 (IL-2) treatment has demonstrated promising antitumour activity in renal cell carcinoma (RCC) and malignant melanoma (MM) and has been shown to induce broad immunological effects. The optimal IL-2 dose and schedule, however, still remain to be defined. We studied a treatment protocol consisting of five repetitive cycles of high-dose recombinant (rh) IL-2 (24 x 10(6) U/m2/day) administered weekly on two consecutive days by continuous intravenous infusion. 17/19 were RCC patients, 2 of whom responded with a complete remission (CR) and 3 with a partial response (PR) (CR + PR: 29%; median response duration of 11.5+ months (range: 3-14 months)). IL-2 induced a pronounced increase of lymphocytes and pro-inflammatory cytokines IL-8, IL-5, gamma-IFN, TNF- alpha and TNF-beta (p < 0.05) that peaked in cycle 3. With subsequent therapy, serum levels of these cytokines, NK, T cells and eosinophils decreased, whereas serum IL-10 levels progressively increased with maximum levels achieved after the fifth week of treatment, suggesting that it may be involved in dampening the inflammatory response induced by IL-2. Absolute numbers of activated T cells and NK cells remained elevated as compared to baseline for at least 4 weeks after treatment cessation. Based on these observations, future scheduling of IL-2 will be done at 3 weekly 2-day cycles separated by a week 4 treatment-free interval in order to increase further the 29% objective response rate achieved in this study.

High-dose continuous intravenous infusion of interleukin-2 therapy for metastatic renal cell carcinoma: The university of Chicago experience

Objectives Treatment of patients with metastatic renal cell carcinoma with high-dose interleukin-2 (IL-2) administered as continuous intravenous (CIV infusion or as bolus injection results in response rates of 15% to 30%; however, toxicities with these regimens have been severe. A trial in which CIV IL-2 was administered at high doses during days 1 to 5 and at reduced doses during days 10 to 20 reported less toxicity without a decrease in response rates. We treated a series of patients with this regimen and our experience is presented. Methods Seventeen patients with metastatic renal cell carcinoma were treated with IL-2 by CIV at a dose of 18 × 10 6 IU/m 2/day for 5 days followed by 4 to 6 days of rest followed by 10 days of CIV IL-2 at a dose of 6 × 10 6 IU/m 2/day. Five patients also received CT-1501R, a pentoxyfylline derivative. Results There was 1 partial responder (PR) and there were no complete responses. The patient with the PR had a 14 × 9 cm 2 renal tumor with metastases to lung, pancreas, and liver. A surgical resection induced a CR, but he relapsed 9 months later. Severe toxicities included hyponatremia (serum sodium of less than 123 mmol/L) (n = 3), biopsy-proven cardiomyopathy (n = 1), creatinine more than 4.5 mg/dL (n = 7), and sudden death (n = 1). Conclusions We conclude that high-dose CIV IL-2 therapy of renal cell carcinoma results in severe toxicity and cannot be recommended for general use. Alternatives need to be developed.

Ischemia-reperfusion-induced muscle damage. Protective effect of corticosteroids and antioxidants in rabbits.

We examined the potential protective effect of pretreatment with corticosteroids or antioxidants (ascorbic acid or allopurinol) in rabbits with reperfusion-induced damage to skeletal muscle after ischemia. 4 hours of limb ischemia induced by a pneumatic tourniquet, followed by reperfusion for 1 hour, caused a considerable amount of ultrastructural damage to the anterior tibialis muscles accompanied by a rise in circulating creatine kinase activity. Pretreatment of animals with depomedrone by a single 8 mg bolus injection led to a preservation of the anterior tibialis structure on both light and electron microscopy. High-dose continuous intravenous infusion with ascorbic acid (80 mg/hr) throughout the period of ischemia and reperfusion also preserved skeletal muscle structure, although allopurinol in various doses had no protective effect. These data are fully compatible with a mechanism of ischemia/reperfusion-induced injury to skeletal muscle, involving generation of oxygen radicals and neutrophil sequestration and activation. They also indicate that damage to human skeletal muscle caused by prolonged use of a tourniquet is likely to be reduced by simple pharmacological interventions.

High-dose continuous venous infusion of interleukin-2: influence of dose and infusion rate on tumoricidal function and lymphocyte subsets

High-dose continuous venous infusion of interleukin-2: influence of dose and infusion rate on tumoricidal function and lymphocyte subsets

932 High dose continuous infusion (CI) ifosfamide without hematopoietic support in heavily pretreated breast cancer (BC) and sarcoma (S) patients

Ifosfamide (IFO) is an oxazophosphorine with a different activity and toxicity profile than cyclophosphamide. Its use together with uroprotective agents has allowed safe administration and dose-escalation. We report the results of a phase II trial of IFO at high doses in heavily pretreated BC and S patients. IFO was administered in a 168 hour CI through a central venous access, for a total dose of 14 g/m2 q3w. MESNA was administered together at equimolar doses. Ondansetron, 8 mg/8 h po was used as antiemetic treatment. No hematopoietic support was used. We included 10 BC and 14 S patients with disease progression during salvage chemotherapy at conventional doses. Mean previous lines of therapy 3 (range 1–5), 20 had received previous treatment with conventional-dose cyclophosphamide or IFO. All had received previous adriamycin. Median age 44 (range 18–62), 12 males and 12 females. Median number of cycle 3 (range 1–8) for a total of 81 cycles of therapy. Worst WHO grade toxic reaction for each patient: grade III–IV leukopenia in 65%, grade III nausea and vomiting in 40%, grade III neurotoxicity in 5%, grade II nephrotoxicity in 5%. Neurologic and renal toxicity were reversible. 9 patients were admitted for neutropenic fever, with two documented septic episodes. Treatment had to be discontinued in 2 patients after 2 cycles (1 renal toxicit); I gastro-intestinal GI-toxicity). 20 patients are evaluable for response (4 did not finish the first cycle of therapy, 3 for early disease progression, 1 for unacceptable GI toxicity). Partial responses in 2/8 (25%) BC, and in 3/12 (25%) S. No complete responses were recorded. 65% had disease stabilization, and 10% had disease progression. 3 with S and 1 BC underwent further high dose chemotherapy with transplantation after assessment of chemotherapy sensitivity with high-dose IFO. Median duration of response was 5 months. Median overall survival was 6 months (range 2–11+). In conclusion, CI of IFO for 168 hours is an active regimen in highly pretreated BC and S. The addition of hematopoietic growth factors and further antiemetic agents could improve the toxicity ofthis regimen. Additionally, this regimen could be combined with non-myelotoxic drugs.

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer

In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m2 for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m2 by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. Patients received a median dose intensity of 5-FU of 2.2 g/m2/week (range, 0.76-3 g/m2/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16-45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand-foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m2 of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m2.

Intensive induction chemotherapy and radiation for organ preservation in patients with advanced resectable head and neck carcinoma.

We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the head and neck. The regimen consisted of intensive chemotherapy followed by radiation therapy alone for patients with good response to treatment. The end points of the study were response rate, organ preservation, toxicity, and survival. Forty-two eligible patients with carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses were enrolled. Induction chemotherapy consisted of three cycles of mitoguazone, fluorouracil (5-FU), and high-dose continuous infusion cisplatin. Patients who had a complete response to chemotherapy, or whose tumor was downstaged to T1N1, were treated with definitive radiation therapy, to a total dose of 66 to 73.8 Gy. Patients with residual disease greater than T1N1 underwent surgery and postoperative radiation. The overall response rate to chemotherapy was 84%, with a 43% complete response rate, and a 68% complete response rate at the primary tumor site. Sixty-nine percent of patients (29 of 42) were initially spared surgery to the primary tumor site, and four of these patients (14%) required neck dissection only, after radiation therapy. These tumor sites included oral cavity, oropharynx, hypopharynx, larynx, and sinuses. Eventually, five of these patients (17%) required salvage surgery and eight patients (28%) had unresectable or metastatic relapses. With a median follow-up duration of 38.5 months, 36% of all patients have had preservation of the primary tumor site and remain disease-free. The median survival duration is 26.8 months. Toxicity was substantial, with a 70% incidence of grade 3 to 4 granulocytopenia and two septic deaths. Organ preservation without apparent compromise of survival was achieved in patients with selected nonlaryngeal sites of head and neck carcinoma. Larger site-specific trials with less toxic regimens conducted in randomized fashion are required to extend these data.